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US9750696B2 - Dissolution enhanced controlled drug delivery system for poorly water soluble drugs - Google Patents

Dissolution enhanced controlled drug delivery system for poorly water soluble drugs Download PDF

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Publication number
US9750696B2
US9750696B2 US14/236,162 US201214236162A US9750696B2 US 9750696 B2 US9750696 B2 US 9750696B2 US 201214236162 A US201214236162 A US 201214236162A US 9750696 B2 US9750696 B2 US 9750696B2
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controlled
dosage form
release
drug
pharmaceutical dosage
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US20150174071A1 (en
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Sandeep Kumar VATS
Kalaiselvan Ramaraju
Romi Barat Singh
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/2045—Polyamides; Polyaminoacids, e.g. polylysine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to controlled-release pharmaceutical dosage forms comprising a solid dispersion of a poorly water-soluble or insoluble drug with improved solubility and thus improved dissolution in an aqueous medium.
  • the invention further discloses a process of preparation of these controlled-release dosage forms.
  • One of the critical problems associated with a poorly water-soluble drug is the very low bioavailability associated with the drug in question. Therefore, directly formulating water-insoluble or poorly soluble drugs into controlled-release systems is likely to lead to failure to achieve the acceptable controlled-release of such drugs.
  • a combination of solubility enhancement and modulating the release is needed to overcome this problem and achieve controlled-release of a water-insoluble or poorly soluble drug.
  • Amorphous materials are thermodynamically unstable and tend to revert to the crystalline form on storage.
  • Another technique is based on particle size reduction, which is intended to increase the contact surface between the drug and the solvent. Size reduction of drugs also causes particle agglomeration due to the static charge. An inadequate control of particle size of the drug can produce variations in the solubilization rate due to agglomeration.
  • Other approaches for increasing the drug dissolution rate of a poorly water-soluble or insoluble drug involve either the incorporation of surfactants/wetting agents or the formation of solid dispersions in water-soluble polymers.
  • solid dispersions are most popular for enhancing the solubility and dissolution.
  • the drug molecules are stabilized in a high-energy state with hydrophilic polymers such as polyethylene glycol, povidone, and polyvinyl alcohol.
  • Hydrophilic polymers such as polyethylene glycol, povidone, and polyvinyl alcohol.
  • Solid dispersions can be prepared using various methods such as spray drying and melt-extrusion.
  • U.S. Pat. No. 7,407,670 assigned to Janssen Pharmaceutica, discloses solid dispersions comprising a first polymer allowing homogeneous or molecular dispersion of a bioactive compound in a matrix and a second polymer enhancing the dissolution of the bioactive compound.
  • U.S. Pat. No. 7,364,752 assigned to Abbott Laboratories, discloses a pharmaceutical composition of ritonavir, wherein ritonavir in the said composition is formulated as a solid dispersion in a matrix including a water-soluble polymer.
  • U.S. Publication No. 2003/0157171 discloses a chitosan-xanthane hydrogel for use as a system capable of modifying the solubilization rates of poorly soluble drugs.
  • a feature that increases the solubility or dissolution of a poorly soluble drug would generally also increase the rate and extent of absorption of the drug. If such a drug gets eliminated rapidly, it becomes necessary to administer the drug frequently (i.e., several times per day) to maintain uniform blood levels. This is an undesirable situation as frequent dosing is inconvenient for the patient and may lead to noncompliance.
  • a first feature to increase solubility or dissolution of the poorly soluble drug and a second feature to slow down and control the rate at which the drug is released from the pharmaceutical dosage form and made available for continuous absorption.
  • the significant benefit that can be achieved is that a dosage regimen with a lower frequency of administration can be designed, thereby resulting in greater patient compliance.
  • U.S. Pat. No. 6,706,283, assigned to Pfizer also discloses controlled-release dosage forms for low solubility drugs by coating the core containing the solid dispersion of the drug with a non-dissolving and non-eroding coating that controls the influx of water to the core, i.e., a controlled-release in the form of a reservoir system.
  • Soluplus® is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. It has an amphiphilic structure and can be regarded as a polymeric solubilizer. This excipient was commercially launched in 2009 and was designed to be used in hot-melt extrusion and to solubilize poorly soluble drugs. It has an average molecular weight (determined by gel permeation chromatography) which is in the range of 90,000 g/mol to 140,000 g/mol.
  • the inventors have successfully developed a controlled-release system which contains the drug as a solid dispersion prepared by using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier, which is summarized and described in detail below.
  • a controlled-release pharmaceutical dosage form of a poorly water-soluble or insoluble drug comprising the solid dispersion of said drug, one or more of controlled-release material, and one or more of pharmaceutically acceptable excipients wherein the said solid dispersion comprises the said drug dispersed in polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
  • the controlled-release pharmaceutical dosage form may be a matrix-type dosage form or a reservoir-type dosage form and may be in the form of hard or soft gelatin capsules, tablets, capsules, caplets, pills, granules or mini-tablets.
  • the controlled-release material may comprise hydrophilic polymers, hydrophobic polymers, water-swellable polymers, hydrophobic materials, or mixtures thereof.
  • the amount of the controlled-release material may comprise from about 2% to about 95% by weight of the dosage form.
  • the drug to polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer ratio weight by weight may vary from 1:1 to 1:5.
  • the pharmaceutically acceptable excipients may comprise one or more of binders, fillers/diluents, disintegrants, anti-adherents, lubricants/glidants, plasticizers, coloring agents and flavoring agents.
  • a process for the preparation of a controlled-release pharmaceutical dosage form of a poorly water-soluble or insoluble drug comprising the solid dispersion of said drug, one or more of controlled-release material, and one or more of pharmaceutically acceptable excipients wherein the said solid dispersion comprises said drug dispersed in polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and wherein the process includes combining the solid dispersion, the controlled-release material, and pharmaceutically acceptable excipient and processing into the dosage form using appropriate toolings.
  • the preferred classes of drugs that may be included in the dosage forms of the invention are, but not limited to, antihypertensives, antianxiety agents, antidepressants, barbiturates, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, antiobesity agents, autoimmune disorders agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's disease agents, antibiotics and antiviral agents.
  • antihypertensives include prazosin, nifedipine, trimazosin, valsartan and doxazosin; a specific example of a blood glucose-lowering agent is glipizide; a specific example of an anti-impotence agent is sildenafil citrate; specific examples of antineoplastics include chlorambucil, lomustine and echinomycin; a specific example of an imidazole-type antineoplastic is tubulazole; specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin and flurbiprofen; a specific example of a barbiturate is phenobarbital; specific examples of antivirals include acyclovir and virazole; specific examples of vitamins/nutritional agents include retinol and vitamin E; specific examples of beta blockers include carvedilol
  • drugs deliverable by the invention are the glucose-lowering drug chlorpropamide, the anti-fungal fluconazole, the anti-hypercholesterolemic atorvastatin calcium, the antipsychotic thiothixene hydrochloride, the anxiolytics hydroxyzine hydrochloride and doxepin hydrochloride, the anti-hypertensive amlodipine besylate, the anti-inflammatories iroxicam, valdecoxib and celicoxib, and the antibiotics carbenicillin indanyl sodium, becampicillin hydrochloride, troleandomycin and doxycycline hyclate.
  • controlled-release includes matrix-type controlled-release pharmaceutical dosage form, reservoir-type controlled-release pharmaceutical dosage form, or combinations of both.
  • the matrix-type dosage forms are those in which the drug is distributed uniformly in one or more of controlled-release materials and reservoir-type compositions utilize polymeric coating over a core comprising the drug.
  • a combination of the reservoir and matrix types includes controlled-release coatings on controlled-release matrices.
  • the controlled-release materials as used in the dosage form may comprise hydrophilic polymers, hydrophobic polymers, water-swellable polymers, hydrophobic material, and mixtures thereof.
  • the controlled-release material may comprise from about 2% to about 95% by weight of the composition.
  • hydrophilic polymers include, but are not limited to, cellulose derivatives, alginates, polyvinyl alcohol, povidone, carbomer, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, polyvinylpyrrolidone, polysaccharide, polyalkylene oxides, polyalkyleneglycol, starch and derivatives, and mixtures thereof.
  • hydrophobic polymers include, but are not limited to, ethyl cellulose, hydroxyethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, polyvinyl acetate, and mixtures thereof.
  • water-swellable polymers include, but are not limited to, polyethylene oxide; poly(hydroxy alkyl methacrylate); poly(vinyl) alcohol; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; Carbopol® carbomer; Cyanamer® polyacrylamides; cross-linked water swellable indene-maleic anhydride polymers; Goodrich® polyacrylic acid; starch graft copolymers; Aqua Keep's® acrylate polymer polysaccharides; Amberlite® ion exchange resins; Explotab® sodium starch glycolate; and Ac-Di-Sol® croscarmellose sodium.
  • hydrophobic materials include, but are not limited to, waxes, fatty acids, fatty alcohols, fatty acid esters, vegetable oil and mineral oil.
  • solid dispersion includes a solution or dispersion of the drug in a polymer such as Soluplus® in a solid state.
  • the solid dispersion improves the solubility and bioavailability of the drug.
  • the drug attains a high-energy state, thus rendering the drug more soluble by facilitating the solvent action for dissolution to occur.
  • the drug to polymer ratio w/w may vary from 1:1 to 1:5.
  • the drug in its pure state may be crystalline or amorphous, but when dispersed in the solid dispersion polymer a major portion of the drug is preferably in an amorphous or non-crystalline state.
  • amorphous state it is meant that the drug may be present in the dispersion in any of three broad classes of forms: (a) in discrete, drug-rich domains; (b) homogeneously distributed therein, i.e., a solid dispersion; or (c) any state or combination of states between the extremes of (a) and (b).
  • the solid dispersion preparation may include a process including dispersing the drug in a polymer using one or more of mechanical mixing, hot-melt, co-melt and congealing, and solvent evaporation techniques.
  • Preparation of a solid dispersion by mechanical mixing includes vigorous mixing, grinding or trituration of the drug and carrier by any means including use of ball milling, hammer mill or air-jet mill.
  • Preparation of the solid dispersion by co-melting and hot-melt extrusion includes direct heating of the physical mixture of the drug and the polymer until the mixture has melted, followed by cooling and solidification under rigorous stirring. The final solid mass may further be crushed, pulverized, and sieved.
  • a homogeneous solution of drug and the polymer is prepared in a solvent, alone or along with other excipients that may or may not be dissolved, followed by solvent removal by precipitation or evaporation.
  • Precipitation is typically induced by contacting the drug/dispersion polymer solution with a non-solvent such as water, a liquid hydrocarbon or super-critical CO 2 .
  • a preferred method of forming the dispersion is by dissolving the drug and the polymer in a common solvent, then removing the solvent by spray-drying the solution.
  • Solvents may include, but are not limited to, water, ethanol, isopropyl alcohol, acetone, chloroform, methanol, methylethylketone, methylene chloride, tertiary butanol, or combination thereof.
  • spray-drying and “spray-coating” in connection with the present invention are used conventionally, and broadly refer to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing a solvent from the mixtures in a vessel such as a spray-drying apparatus or a fluidized bed or pan-coater where there is a strong driving force for evaporation of the solvent from the droplets.
  • a vessel such as a spray-drying apparatus or a fluidized bed or pan-coater where there is a strong driving force for evaporation of the solvent from the droplets.
  • spray-coating the droplets impinge on a particle, bead, pill, tablet, or capsule, resulting in a coating comprising the solid amorphous dispersion.
  • Solid dispersions with Soluplus® can be formulated into solid dosage forms, e.g., hard gelatin capsules, compressed into tablets and layered on an inert core. The poorly soluble drug and Soluplus® need to be first dissolved in an appropriate solvent. This solution then can be sprayed onto inert pellets (nonpareils).
  • a surfactant may also be included in the solid dispersion.
  • Surfactants may include both non-ionic and ionic (cationic, anionic and zwitter-ionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and their derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4-150 mono dilaurate, and polyethylene glycol-20 glyceryl stearate; alcohol-oil transesterification products, for example, polyethylene glycol-6 corn oil; polyglycerized fatty acids, for example, polyglyceryl-6 pentaoleate; propylene glycol I fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol-20 sorbit
  • the dosage form further includes pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients such as binders, fillers/diluents, disintegrants, anti-adherents, lubricants/glidants, plasticizers, coloring agents and flavoring agents.
  • binders include, but are not limited to, acacia, sodium alginate, starch, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, veegum, larch arabolactan, polyethylene glycols, ethylcellulose, water, alcohols, waxes, polyvinylpyrrolidone such as PVP K90, or mixtures thereof.
  • fillers/diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrin or other polysaccharides, sorbitol, inositol, or mixtures thereof.
  • Suitable examples of disintegrants include, but are not limited to, starches, clays, cellulose derivatives including crosscarmellose, gums, algins, various combinations of hydrogencarbonates with weak acids (e.g., sodium hydrogencarbonate/tartaric acid or citric acid) crosprovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum HV, natural sponge, bentonite, or mixtures thereof.
  • weak acids e.g., sodium hydrogencarbonate/tartaric acid or citric acid
  • crosprovidone sodium starch glycolate
  • agar e.g., cation exchange resins
  • citrus pulp e.gum HV
  • natural sponge natural sponge
  • bentonite or mixtures thereof.
  • Suitable examples of lubricants/glidants include, but are not limited to, talc, magnesium stearate, calcium stearate, steeric acid, hydrogenated vegetable oils, sodium benzoate, sodium chloride, leucine, carbowax 4000, magnesium lauryl sulfate, colloidal silicon dioxide, and mixtures thereof.
  • plasticizers include, but are not limited to, phosphate esters; phthalate esters; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glyceride and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate; acetyl triethyl citrate; Castor oil; diacetylated monoglycerides; dipropylene glycol salicylate glycerin; glyceryl cocoate; mono- and di-acetylated monoglycerides; phthalyl glycolate; diocyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl; polyethylene glycol succinate; phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohol
  • coloring agents include, but are not limited to, water-soluble FD&C dyes and mixtures thereof with corresponding lakes and direct compression sugars such as Di-Pac from Amstar.
  • colored dye migration inhibitors such as tragacanth, acacia or attapulgite talc may be added.
  • Specific examples include calcium carbonate, chromium-cobalt-aluminium oxide, ferric ferrocyanide, ferric oxide, iron ammonium citrate, iron (III) oxide hydrated, iron oxides, magnesium carbonate, and titanium dioxide.
  • controlled-release dosage forms according to the present invention may take the form of tablets, which may be produced by compressing the final mix of granules and/or powders into tablets.
  • controlled-release dosage forms according to the present invention may take the form of pellets which are coated with the solid dispersion of drug followed by the controlled-release coating.
  • the coating of the pellets may be carried out in the Wurster coating system or in any other conventional coating system.
  • the final pellets may be filled into capsules or compressed into tablets.
  • controlled-release pharmaceutical dosage form can optionally have one or more coatings, which are functional or non-functional.
  • Suitable examples of polymers useful for coating include, but are not limited to, cellulose acetate, ethyl cellulose, polyamide, polyethylene, polyethylene tereppthalate, polypropylenem polyurethane, polyvinyl acetate, polyvinyl chloride, polyhydroxybutyrate, polyhydroxyvalerate, polylactic acid or polyglycolic acid and copolymers thereof, copolymers such as ethylene vinyl acetate (EVA), styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS).
  • EVA ethylene vinyl acetate
  • SBS styrene-butadienestyrene
  • SIS styrene-isoprene-styrene
  • the controlled-release pharmaceutical dosage form may be prepared by one of more of the following processes:
  • a suitable process of preparation of the dosage form includes the following steps:
  • Another suitable process of preparation of the dosage form includes the following steps:
  • Another suitable process of preparation of the dosage form includes the following steps:
  • Another suitable process of preparation of the dosage form includes the following steps:

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US14/236,162 2011-08-01 2012-08-01 Dissolution enhanced controlled drug delivery system for poorly water soluble drugs Expired - Fee Related US9750696B2 (en)

Applications Claiming Priority (3)

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IN2175/DEL/2011 2011-08-01
IN2175DE2011 2011-08-01
PCT/IB2012/053945 WO2013018050A2 (fr) 2011-08-01 2012-08-01 Système d'administration de médicaments à libération contrôlée et dissolution améliorée pour médicaments peu solubles dans l'eau

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ZA (1) ZA201400938B (fr)

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WO2013191668A1 (fr) * 2012-06-22 2013-12-27 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions pour la prévention de l'hypertension comprenant du soluplus
WO2014011830A1 (fr) 2012-07-12 2014-01-16 Mallinckrodt Llc Compositions pharmaceutiques de dissuasion d'abus à libération prolongée
WO2015000853A1 (fr) * 2013-07-05 2015-01-08 Synthon B.V. Composition pharmaceutique comprenant une dispersion solide de tadalafil
US20170119678A1 (en) * 2014-06-23 2017-05-04 Hetero Research Foundation Extended release compositions of carvedilol phosphate
WO2016198983A1 (fr) 2015-06-09 2016-12-15 Bend Research Inc. Formulations pour obtenir une dissolution rapide d'un médicament à partir de dispersions séchées par pulvérisation dans des capsules
ITUB20161016A1 (it) * 2016-02-24 2017-08-24 Emenem Srl Composizioni farmaceutiche o cosmetiche comprendenti un polimero e un promotore di assorbimento per il rilascio controllato di principi attivi

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EP2739269A2 (fr) 2014-06-11
WO2013018050A3 (fr) 2013-05-30
US20150174071A1 (en) 2015-06-25
WO2013018050A2 (fr) 2013-02-07
ZA201400938B (en) 2015-04-29
AU2012291631A1 (en) 2014-02-27

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